“Diabetes mellitus” (or diabetes) is one of the most prevalent diseases in the world today. Individuals suffering from diabetes have been divided into two classes, namely type I or insulin-dependent diabetes mellitus and type II or non-insulin-dependent diabetes mellitus (NIDDM). Non-insulin-dependent diabetes mellitus (NIDDM) accounts for approximately 90% of all diabetics, and is estimated to affect 12 to 14 million adults in the United States alone (6.6% of the population).
NIDDM is characterized both by fasting hyperglycaemia and exaggerated postprandial increases in plasmatic glucose levels. NIDDM is associated with a variety of long-term complications, including microvascular diseases, such as retinopathy, nephropathy and neuropathy, and macrovascular diseases, such as coronary heart disease.
Numerous studies in animal models show a causal relationship between long-term complications and hyperglycaemia. Recent results obtained by the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study have for the first time demonstrated this relationship in man by showing that insulin-dependent diabetics have a substantially lower risk of development and progression of these complications if they are subjected to tighter glycaemic control. Tighter control is also expected to benefit NIDDM patients.
Current therapies used for the treatment of NIDDM patients involve both controlling lifestyle risk factors and pharmaceutical intervention. First-line therapy for NIDDM patients is usually a strictly controlled regimen of diet and exercise, since an overwhelming number of NIDDM patients are overweight or obese (≈67%) and since loss of weight can improve insulin secretion and insulin sensitivity, and lead to normoglycaemia.
Normalization of blood glucose takes place in fewer than 30% of these patients due to poor compliance and poor response. Patients suffering from hyperglycaemia not controlled by diet alone are subsequently treated with insulin or oral hypoglycaemiants. At the present time, insulin secretors (sulfonylureas and glinides), biguanides (metformin) and insulin sensitizers (glitazone) are the only classes of oral hypoglycaemiants available for NIDDM. Treatment with sulfonylureas leads to an effective reduction in blood glucose in only 70% of patients and only 40% after 10 years of therapy. Patients for whom diet and sulfonylureas have no effect are then treated with daily insulin injections in order to establish adequate glycaemic control.
Although sulfonylureas represent a major therapy for NIDDM patients, four factors limit their overall success. Firstly, as indicated above, a large proportion of the NIDDM population does not respond adequately to sulfonylurea therapy (i.e. primary failures) or becomes resistant (i.e. secondary failures). This is particularly true in the case of NIDDM patients with advanced NIDDM, due to the fact that these patients suffer from severely impaired insulin secretion. Secondly, sulfonylurea therapy is associated with an increased risk of severe hypoglycemic episodes. Thirdly, chronic hyperinsulinemia is associated with an increase in cardiovascular diseases, although this relationship is considered controversial and unproven. Finally, sulfonylureas are associated with weight gain, which leads to worsening of peripheral insulin sensitivity and may consequently accelerate the progression of the disease.
Recent results from the UK Diabetes Prospective Study also show that patients subjected to maximal therapy of a sulfonylurea, metformin, or a combination of the two, were unable to maintain normal fasting glycaemia over the six-year period of the UK Prospective Diabetes Study, 16. Diabetes, 44, 1249-158 (1995). These results also illustrate the great need for alternative therapies. Three therapeutic strategies that could provide additional benefits as regards the health of NIDDM patients beyond the currently available therapies include medicaments that would: (i) prevent the onset of NIDDM; (ii) prevent diabetic complications by blocking harmful events precipitated by chronic hyperglycaemia; or (iii) normalize glucose levels or at least reduce glucose levels below the threshold reported for microvascular and macrovascular diseases.
Hyperglycaemia in the case of NIDDM sufferers is associated with two biochemical abnormalities, namely insulin resistance and impaired insulin secretion. The relative roles of these metabolic abnormalities in the pathogenesis of NIDDMs have been the subject of numerous studies over the last several decades. Studies performed on the offspring and siblings of NIDDM patients, on monozygotic and dizygotic twins, and on ethnic populations with a high incidence of NIDDM (for example Pima Indians), strongly support the hereditary nature of the disease.
Despite the presence of insulin resistance and impaired insulin secretion, fasted blood glucose (FBG) levels remain normal in the case of pre-diabetic patients on account of a state of compensatory hyperinsulinemia. Eventually, however, the insulin secretion is inadequate and leads to fasting hyperglycaemia. Over time, the insulin levels decrease. Progression of the disease is characterized by increasing FBG levels and decreasing insulin levels.
Numerous clinical studies have attempted to define the primary defect involved during the progressive increase in FBG levels. The results of these studies show that excessive hepatic glucose output (HGO) is the first reason for the increase in the FBG levels, with a significant correlation found for HGO and FBG once the FBG levels exceed 140 mg/dL. Kolterman et al., J. Clin. Invest., 68, 957, (1981); DeFronzo, Diabetes, 37, 667, (1988).
HGO comprises glucose derived from the breakdown of hepatic glycogen (glycogenolysis) and glucose synthesized from 3-carbon precursors (gluconeogenesis). A large number of radioisotopic studies, and also several studies using 13C-NMR spectroscopy, show that gluconeogenesis accounts for 50% to 100% of the glucose produced by the liver in the post-absorptive state and that the gluconeogenesis flux is excessive (2- to 3-fold) in the case of NIDDM patients. Magnusson et al., J. Clin. Invest, 90, 1323-1327, (1992); Rothmann et al., Science, 254, 573-76, (1991); Consoli et al., Diabetes, 38, 550-557, (1989).
Gluconeogenesis from pyruvate is a highly regulated biosynthetic pathway that requires eleven enzymes. Seven enzymes catalyse reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyse reactions specific to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Overall flux is controlled throughout the biosynthetic pathway by the specific activities of these enzymes, the enzymes that catalyse the corresponding steps in the glycolytic direction, and by substrate availability. Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoids, epinephrine) co-ordinatively regulate the enzymatic activities in the gluconeogenesis and glycolysis processes by means of gene expression and post-translational mechanisms.
Among the four enzymes specific to gluconeogenesis, fructose-1,6-bisphosphatase (referred to hereinbelow as “FBPase”) is a very suitable target for a gluconeogenesis inhibitor based on efficacy and safety considerations. Studies show that nature uses the FBPase/PFK cycle as a main control point (metabolic switch) for determining whether the metabolic flux is proceeding in the direction of glycolysis or gluconeogenesis. Claus et al., Mechanisms of Insulin Action, Belfrage, P. Editor, pp. 305-321, Elsevier Science, (1992); Regen et al., J. Theor. Bio., 635-658, (1984); Pilkis et al., Annu. Rev. Biochem., 57, 755-783, (1988). FBPase is inhibited by fructose-2,6-bisphosphate in the cell. Fructose-2,6-bisphosphate binds to the substrate site of the enzyme. AMP binds to an allosteric site on the enzyme.
Synthetic FBPase inhibitors have also been reported. Maryanoff has reported that fructose-2,6-bisphosphate analogues inhibit FBPase by binding to the substrate site. J. Med. Chem., 106, 7851, (1984); U.S. Pat. No. 4,968,790, (1984). However, these compounds show relatively low activity and do not inhibit glucose production in hepatocytes, undoubtedly on account of poor cell penetration.
Numerous fructose-1,6-bisphosphatase inhibitors that are useful in the treatment of diabetes have been reported:                Gruber has reported that some nucleosides can lower blood glucose in the whole animal by inhibition of FBPase (EP 0 427 799 B1). These compounds exert their activity by first performing a phosphorylation to the corresponding monophosphate;        Gruber et al. (U.S. Pat. No. 5,658,889) have described the use of inhibitors of the AMP site of FBPase for the treatment of diabetes;        Dan et al. (WO 98/39344, WO 00/014095) have described novel purines and heteroaromatic compounds as FBPase inhibitors;        Kasibhatla et al. (WO 98/39343) have described novel benzimidazolyl-phosphonates as FBPase inhibitors;        Reddy et al. (WO 98/39342) have described novel indoles and azaindoles as FBPase inhibitors;        Jaing et al. (WO 01/047935) have described bisamidate-phosphonates as specific FBPase inhibitors for the treatment of diabetes;        Bookser et al. (WO 01/066553) have described heterocycle phosphates as specific FBPase inhibitors for the treatment of diabetes.        
Imidazolecarboxamide derivatives have previously been described as synthetic intermediates or as anti-inflammatories (cf. EP 1 092 718, FR 2 208 667, FR 2 149 329, FR 2 181 728).